Abstract 15739: The High Molecular Weight Isoforms of Fibroblast Growth Factor 2 are Necessary for Postischemic Hindlimb Functional Recovery and Revascularization
Growth factor-mediated neo- or revascularization is an alternative to treatment for ischemic vascular diseases (coronary or peripheral). Fibroblast growth factor 2 (FGF2), implicated in a variety of physiological processes including post-natal vascular growth and development (angiogenesis and arteriogenesis), is expressed as several high molecular weight protein isoforms (HMW) and a low molecular weight (LMW) protein isoform. Results from placebo-controlled clinical trials with angio- or arteriogenesis stimulators including LMW FGF2 have not been beneficial. To date, the role of the HMW FGF2 isoforms in chronic ischemia-induced revascularization are unknown. The goal of this study was to determine whether the HMW isoforms of FGF2 were necessary for ischemia-induced revascularization. Mice with complete or isoform-specific ablation of FGF2 were subjected to chronic hindlimb ischemia, using the contralateral limb as a sham treatment. Hindlimb function, tissue necrosis, vascular density, vascular architecture and FGF2 protein isoform expression were assessed at various times of chronic ischemia. The presence of only the HMW isoforms resulted in improved limb function as early as 7 days of chronic ischemia compared to wildtype (WT) limbs (p<0.05) while expression of the LMW isoform alone caused a 3x delay in limb function recovery. In addition, there was no toe or limb necrosis detected in the presence of only the HMW isoforms (0 of 25), but expression of the LMW isoform resulted in a 22% (7 of 31) incidence of necrosis. Moreover, the HMW isoforms stimulated an increase in capillary and arteriole density and normal vascular morphology by 42 days ischemia (p<0.05), while no change in capillary numbers and a decrease in arteriole growth and a tortuous vessel morphology was observed when only the LMW isoform of FGF2 was expressed compared to WT. Furthermore, significant alterations in the protein expression of FGF2 HMW and LMW isoforms were observed between genotypes as well as sham vs. ischemic limb. These findings suggest that the HMW isoforms of FGF2 are necessary and sufficient to induce revascularization and preserve limb function and tissue viability in response to chronic ischemia.
- © 2012 by American Heart Association, Inc.